The present invention relates to use of indazol methoxyalkanoic acids for preparing a pharmaceutical composition active in the treatment of disorders characterized by production of MCP-1 protein.
European patent EP-B-0 382 276 describes a compound having the formula: 
wherein
R and Rxe2x80x2, the same as or different from each other, are H or an alkyl having from 1 to 5 carbon atoms,
Rxe2x80x2xe2x80x3 is H or an alkyl having from 1 to 4 carbon atoms,
and, when Rxe2x80x2xe2x80x3 is H, salts thereof with pharmaceutically acceptable organic or inorganic bases.
The above-mentioned patent additionally specifies that the compound having the formula (I) possesses an analgesic activity.
Furthermore, European patent EP-B-0 510 748 describes the use of the compound having the formula (I) for preparing a pharmaceutical composition active in the treatment of autoimmune diseases.
It has now been found that the compound having the formula (I) is also active in reducing production of MCP-1 protein.
As already known, MCP-1 protein (Monocyte Chemotactic Protein-1) is a chemokine belonging to the xcex2 subfamily of the chemokines. It possesses a strong chemotactic activity for monoctyes and also acts on T lymphocytes, mastocytes and basophils.
Other chemokines belonging to the xcex2 subfamily are, for example: MCP-2 (Monocyte Chemotactic Protein-2), MCP-3, MCP4, MIP-1xcex1 and MIP-1xcex2, RANTES and protein 1309.
The xcex2 subfamily differs in structure from the a subfamily; in fact, whilst the first two cysteines of the chemokines of the a subfamily are separated by an interposed amino acid, the first two cysteines of the xcex2 subfamily are adjacent to each other. MCP-1 is produced by several types of cells (leucocytes, platelets, fibroblasts, endothelial cells).
Of all the known chemokines, MCP-1 shows the highest specificity in respect of monocytes and macrophages, for which it is not only an attracting factor but also a stimulus of activation, thus inducing a process of production of superoxides and arachidonic acid, as well as being a stimulus of amplification of phagocytic activity.
Secretion of chemokines in general and especially of MCP-1 is typically induced by numerous factors such as, for example, interleukin-1 (IL-1), interleukin-2 (IL-2), TNFxcex1 (Tumor Necrosis Factor xcex1), xcex3-interferon and bacterial lipopolysaccharide (LPS).
In the human, MCP-1 has been found in a large number of diseases with acute or chronic course not classified in homogeneous categories by traditional medicine: for example, interstitial lung disorders (ILD), vasculitis and atherosclerosis.
In interstitial lung disorders, MCP-1 released by pulmonary endothelial cells, attracts and activates competent cells with consequent release of mediators which damage the alveolar structures of the lung.
In vasculitis, MCP-1 is released by the endothelial cells of the vasa following harmful stimuli and attracts and activates monocytes and other cell types which become responsible for damage to the vascular wall.
In atherosclerosis, MCP-1 is produced by the vascular endothelium following damage to the vascular smooth muscle cells. MCP-1 attracts monocytes which initially adhere to the arterial wall and then migrate through the walls, contributing to formation of atheroma by stimulating proliferation of smooth muscle cells.
The therapies currently used in these disorders, because they act upstream of the pathological phenomena, are aspecific and very often have numerous and at times serious side effects.
The above-mentioned therapies, moreover, only enable temporary remission of the pathological phenomena to be obtained and their high toxicity prevents their use for prolonged periods of the kind necessary on the other hand in diseases of chronic type.
For atherosclerosis, in particular, the drugs currently used only act on certain factors which contribute to formation of the atheroma, such as hypercholesterolaemia or hypertension, whilst having no effect on the target of the pathological process, i.e. the vascular wall.
Chemotactic factors in general and MCP-1 in particular are also very important in cases where complications occur following surgical interventions such as, for example, angioplasty, atherectomy, circulatory recovery techniques, transplants, organ replacements, tissue replacements and prosthetic implants. Onset of such complications often makes it necessary for the patient to undergo further intensive therapies or even a new intervention.
U.S. Pat. No. 5,571,713 claims a composition comprising an MCP-1 antisense oligonucleotide for in vitro inhibition of production of MCP-1 by mononuclear human cells and smooth muscle.
There is therefore still a strong need for a pharmaceutical composition which is effective in the treatment of disorders characterized by production of MCP-1, e.g. atherosclerosis, vasculitis, interstitial lung disorders due to postoperative complications of cardiovascular surgery, in transplants or organ or tissue replacements and in prosthetic implants.
The object of the present invention is therefore use of a compound having the formula 
where
R and Rxe2x80x2, the same as or different from each other, are H or an alkyl having from 1 to 5 carbon atoms,
Rxe2x80x2xe2x80x3 is H or an alkyl having from 1 to 4 carbon atoms,
and, when Rxe2x80x2xe2x80x3 is H, salts thereof with pharmaceutically acceptable organic or inorganic bases,
for preparing a pharmaceutical composition for the treatment of a disorder selected from the group comprising atherosclerosis, vasculitis, interstitial lung disorders, postoperative complications in cardiovascular surgery, in transplants or organ or tissue replacements and in prosthetic implants, and characterized by an increased production of MCP-1 protein.
Preferably Rxe2x80x2xe2x80x3 is H, whilst Rxe2x95x90Rxe2x80x2=CH3; this product is hereinafter called xe2x80x9cbindaritxe2x80x9d.
Preferably the pharmaceutical compositions according to the present invention are prepared in suitable dosage forms comprising an effective dose of at least one compound having the formula (I) or a salt thereof with a pharmaceutically acceptable base and at least one pharmaceutically acceptable inert ingredient.
Examples of suitable dosage forms are tablets, capsules, coated tablets, granules, solutions and syrups for oral administration; medicated plaster patches for transdermal administration; suppositories for rectal administration and sterile solutions for administration by the injectable, aerosol or ophthalmic routes.
Further suitable dosage forms are slow release and liposome based forms, for either the oral or the injectable routes.
The dosage forms may also contain other conventional ingredients, for example: stabilising preservatives, surfactants, buffers, salts for regulation of osmotic pressure, emulsifiers, sweeteners, coloring agents, flavourings, and the like.
If required by particular therapies, the pharmaceutical composition according to the present invention may contain other pharmacologically active ingredients whose concomitant administration is therapeutically useful.
The amount of compound having the formula (I) or of a salt thereof with a pharmaceutically acceptable base in the pharmaceutical composition according to the present invention may vary within a wide range depending on known factors such as, for example, the type of disease to be treated, the severity of the disease, the patient""s body weight, the dosage form, the chosen administration route, the number of daily administrations and the efficacy of the selected compound having the formula (I). The optimum amount can nevertheless easily and routinely be determined by a person skilled in the art.
Typically, the amount of compound having the formula (I) or of a salt thereof with a pharmaceutically acceptable base in the pharmaceutical composition according to the present invention will be such that it ensures an administration level of from 1 to 100 mg/kg/day. Preferably the administration level is of from 5 to 50 mg/kg/day or still more preferably of from 2 to 20 mg/kg/day.
The dosage forms of the pharmaceutical composition according to the present invention may be prepared according to techniques which are known to the pharmaceutical chemist, comprising mixing, granulation, compression, dissolution, sterilization and the like.